Process for preparing thiazoline azetidinones

ABSTRACT

Imino halides of 3-amido-2-halo-1-(1&#39;&#39;-protected carboxy-2&#39;&#39;methyl-1&#39;&#39;-propenyl)-4-azetidinones, and a process for preparing bicyclic thiazoline azetidinones by reacting the above imino halides with hydrogen sulfide or a thioalkanoate ion in the presence of a base in an aprotic solvent. The thiazoline azetidinone compounds are useful in processes for making amidothiazole compounds which are useful as antibacterial and antifungal agents.

United States Patent [1 1 Kukolja et al.

[ Apr. 29, 1975 PROCESS FOR PREPARING THIAZOLINE AZETIDINONES [75]Inventors: Stjepan Kukolja, lndianapolis;

Steven R. Lammert, Greenwood, both of Ind.

[73] Assignee: Eli Lilly and Company, lndianapolis,

Ind.

[22] Filed: May 16, 1974 [2]] Appl. No.: 470,501

Related 0.5. Application Data [62] Division of Scr. No. 182,556 Sept.21, l97l. Pat.

[52] U.S. Cl 260/306.7 C [51 Int. Cl. C07d 91/42; C07d 99/10 [58] Fieldof Search 260/306.7 C

[56] References Cited UNITED STATES PATENTS 3 68l 38() 8/l972 Cooper260/3067 C Primary Examiner-Alton D. Rollins Attorney, Agent. orFirm-William C. Martens, Jr.; Everet F. Smith [5 7] ABSTRACT lminohalides of 3-amido-2-halo-1-(l -protected carboxy-2-methyl-l-propenyl)-4-azetidinones, and a process for preparing bicyclicthiazoline azetidinones by reacting the above imino halides withhydrogen sulfide or a thioalkanoate ion in the presence of a base in anaprotic solvent. The thiazoline azetidinone compounds are useful inprocesses for making amido-thiazole compounds which are useful asantibacterial and antifungal agents.

4 Claims, No Drawings PROCESS FOR PREPARING TIIIAZOLINE AZETIDINONESThis is a division of application Ser. No. 182,556,

filed Sept. 21, 1971 now US. Pat. No. 3,832,347 issued Aug. 27, 1974.

INTRODUCTION BACKGROUND OF THE INVENTION In U.S. Pat. No. 3,840,556there are described and claimed some compounds of the formula wherein R,is an acyl group selected from the group consisting of a group of theformula wherein Q is selected from the group consisting ofhydrogen andone or more substituents selected from the group consisting of C, to Calkyl, C, to C alkoxy, nitro, halogen, carboxy and trifluoromethyl and nis zero or an integer from 1 to 5; a group of the formula wherein Q andn are as defined above; a group of the formula wherein Q is as definedabove; and, a group of the formula wherein R, is hydrogen or C, or Calkyl; R is hydrogen, or, R, and R together with the nitrogen atom towhich they are bonded define an imido group selected from the groupconsisting of phthalimido and succinimido; R is selected from the groupconsisting of C, C, alkyl, trichloroethyl, benzyl, p-nitrobenzyl,p-methoxybenzyl, benzhydryl, phthalimidomethyl and phenacyl; and, X isselected from the group consisting of chloro, bromo and C to Calkanoyloxy.

Compounds of that type are prepared by reacting a penicillin ester witha source of positive halogen, e.g., elemental chlorine, in a molar ratioof the source of positive halogen to the penicillin ester greater than1.75 in an aprotic solvent. The reaction therein involves a selectiveopening of the S,C bond of the thiazolidine ring moiety of thepenicillin ester.

In US. Pat. No. 3,594,389, Robin D. G. Cooper describes and claims somenew substituted thiazoles which are useful as antibiotics and antifungalagents. Cooper prepared those compounds by treating a thiazolineazetidinone with an acid or a base to open the B-lactam ring. Thethiazoline azetidinone was obtained by treatment of a penicillinsulfoxide with triphenyl phosphine or a trialkyl phosphite. In US. Pat.No. 3,705,892, Robin D. G. Cooper claimed the new thiazoline azetidinonecompounds. These thiazoline azetidinone compounds have someantibacterial and antifungal activity of their own. They are also ofinterest for use in synthetic chemical processes for preparingamido-thiazole antibacterial and antifungal substances.

It is an object of this invention to provide some new imino-halidecompounds which are useful for making thiazoline azetidinones.

It is another object of this invention to provide a new process formaking thiazoline azetidinone compounds.

It is a more specific object of this invention to provide new iminohalides of 3-amido-2-halo-l-( l esterified-carboxyl-Z'-methyl-l"propenyl)-4- azetidinones, and a process for converting imino halidesof this type to thiazoline azetidinone esters.

SUMMARY OF THE INVENTION By this invention, we have discovered that new,readily isolatable, imino halides of the formula can be prepared bytreating a compound of the formula wherein, in the above formulae, R, R,Y and Z are as defined below, with phosphorus pentachloride, or anequivalent halogenating agent, in the presence of a hydrogen halideabsorber in an aprotic liquid solvent at a temperature below about 30C.The imino halides are used in a new process for preparing bicyclicthiazoline azetidinone compounds of the formula COOR I o CHa T QCIYZIM VI R COOR wherein R and R are defined hereinbelow. Those thiazolecompounds are claimed by Cooper in his US. Pat. No. 3,594,389, issuedJuly 20, 1971. The thiazoles are useful an antibiotics against fungi andbacteria.

DETAILED DESCRIPTION OF THE INVENTION This invention provides iminohalides of formula II above where R is a. C, to C -alkyl,

b. C to C -cycloalkyl,

c. C, to C -alkenyl,

d. one of the above alkyl, cycloalkyl, or alkenyl groups substitutedwith C, to C -alkyloxy, chlorine, bromine, cyano, or carbo-C, to C-alkyloxy;

wherein in each such group O is hydrogen, chloro, bromo, C, to C -alkyl,C, to C -alkyloxy, nitro or cyano; and X is oxygen or a carbon to carbonbond, m is an integer of from 0 to 2, and n is an integer of from I to2;

Z is chlorine or bromine; and

R is C, to C,-normal or iso-alkyl, C to C -tert-alkyl, C to C-tert-alkenyl, C to C -tert-alkynyl, benzyl, methoxybenzyl, nitrobenzyl,benzhydryl, phthalimidomethyl, succinimidomethyl, phenacyl,2,2,2-trichloroethyl or methoxymethyl.

These imino halides are prepared by treating a compound of formula IIIwherein R and R are as defined above and Y is chlorine or bromine, witha halogenating agent such as phosphorus pentachloride, phosphoruspentabromide, or the like under substantially anhydrous conditions inthe presence of an acid binding agent such as a tertiary amine, e.g.,quinoline, pyridine, dimethylaniline, or diethylaniline. The formationof the imino-halide (formula II) is preferably effected in an inertorganic solvent such as methylene chloride, dichloroethane, chloroform,carbon tetrachloride, tetrachloroethane, nitromethane, diethyl ether,and the like, preferably at temperatures below 0C., such as l0C. to 76C.

The compounds of formula III which are used to prepare these new iminohalides (II) can be obtained by treating a 6-acylamino penicillin esterwith a source of positive halogen in an aprotic solvent. That process isclaimed in Kukolja US. Pat. No. 3,832,347. Briefly, by that process, thepenicillin ester is treated with the source of positive halogen such aschlorine, bromine, mixed halogens, sulfuryl chloride, sulfuryl bromide,N- halogenamides and N-chlorobenzotriazole and alkanoyl hypohalides toeffect selective cleavage or opening of the thiazolidene ring moiety ofthe penicillin at the S,-C bond, and the resulting formation of acompound of formula III, when the mole ratio of the source of positivehalogen to the penicillin ester is greater than 1.5. It is preferredthat this mole ratio be greater than 2 for most efficient production ofthe compounds of formula III. A detailed example for the preparation ofsuch starting materials appears in Example 1, part A, below.

As the penicillin ester starting material, use is preferably made of-acylamido penicillin esters of the formula wherein R and R are asdefined above. However, as

will be appreciated by those skilled in the art, since R amd R do notenter into the reaction, R and R can be 1 e 5 S 2 CHE' 'CH/ CHz Thus,penicillin V (i.e., phenoxymethyl penicillin) has the structure COOH , nCeHs-O-CHz-C-N and can be named6-phenoxyacetamido-2,Z-dimethylpenam-S-carboxylic acid.

Representative penicillin esters which can be used as starting materialsfor preparing the imino halide and thiazoline azetidine products of thisinvention include Methyl 6-acetamido-2,2-dimethylpenam-3- carboxylate,sec-Butyl 6-octanoylamido-2,2-dimethylpenam-3- carboxylate, Propyl6-cyclohexylacetamido-2,Z-dimethylpenam- 3-carboxylate, tert-Butyl6-propenoylamido-2,2-dimethylpenam-3- carboxylate, tert-Pentenyl6-heptenoylamido-2,2-dimethyl-3- carboxylate,

Q is hydrogen, chloro, bromo, C, to C -alkyl, C, to C alkyloxy, nitro,or cyano;

X is oxygen or a carbon to carbon bond;

m is an integer of from 0 to 2;

n is an integer of from 1 to 2;

R is hydrogen, C, to C -normal or iso-alkyl, C, to C tert-alkyl, C toC,,-tert-alkenyl, C to C -tert-alkynyl, benzyl, methoxybenzyl,nitrobenzyl, benzhydryl, phthalimidomethyl Succinimidomethyl, phenacyl,trichloroethyl or methoxymethyl is prepared by treating a compound ofthe formula (ll) wherein R and R are as defined above and Z is chlorineor bromine with hydrogen sulfide or a thioalkanoyl radical in thepresence of a base in an aprotic solvent at a temperature below about C.

lf hydrogen sulfide is the selected bivalent sulfur supplying material,it can be bubbled into the liquid reaction medium containing thecompound of formula II and a basic material. Alternatively, it can besupplied as an alkali metal salt thereof, e.g. Na-SH or K-SH. A molarratio of at least 2 moles of base to 1 mole of hydrogen sulfide shouldbe used. Alkali metal hydroxides, or basic salts such as sodiumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonatecan be used.

In place of part or all of the hydrogen sulfide, a source ofthioalkanoate [HS-C(O)R"] ions can be used. The preferred thioalkanoateions are those wherein R" is an alkyl group having from 1 to 12 carbonatoms. The thioalkanoate ion can be supplied to the medium as the acidor as a salt thereof such as the sodium or potassium salts ofthioformic, thioacetic, thiopropionic, thiobutyric, thiopentanoic,thiohexanoic, thioheptanoic, thiooctanoic, thiodecanoic, thiododecanoicacids. Other bases which can be used in the reaction mixture includeammonia, and methylammonium, dimethylammonium, trimethylammoniumcationic salts of weak acids.

The reaction is conducted in an aprotic solvent such as methylenechloride, chloroform, carbon tetrachloride, tetrahydrofuran,N,N-dimethylformamide, dimethylsulfoxide, benzene, toluene, xylene,heptane, dioxane, and the like.

The reaction can be conducted in the liquid state at temperatures belowabout 70C., preferably below 50C. Above 70C., the yields are lower andthe reaction product becomes complex.

When the reaction is completed the thiazoline azetidinone product can beseparated from the mixture by conventional means. If the hydrohalidesalt of the base is filterable, it is separated e.g., by filtration orcentrifugation. The filtrate can then be evaporated to remove thesolvent and the residue can be dissolved in a solvent such as ethylacetate or benzene, and chromatographed to purify the product. Theseproducts have been obtained as oils but some of them may be obtainableas amorphous or crystalline solids depending on the solvent systems andthe degree of purity. Separation of the products over silica gel columnusing a benzene/ethylacetate mixture as an eluant, and fractionating theliquid products has permitted the obtaining of the products as oils.Spectral data were consistent with the indicated structures.

The thiazoline azetidinone esters of this invention are useful formaking the acids, by conventional deesterification procedures. Theesters may be deesterified by treatment thereof with mild acid such astrifluoroacetic acid, zinc in formic, acetic, or hydrochloric acid for afew minutes, or by hydrogenating the ester in the presence of apalladium or platinum catalyst on a barium sulfate or carbon carrier atautogeneous pressure. The thiazoline azetidinone acids and some of theesters are useful in the treatment of plant diseases. For example, thetrichloroethyl ester and the acid having the structure of formula IVwhere R is phenoxymethyl and R is hydrogen or trichloroethyl are activeagainst Fusarium Root Rot. This activity is demonstrated by applying thecompound at a broadcast rate of 40 pounds per acre to Fusarium infestedsoil and then planting Bountiful variety bean seeds in the soil. After14 days, the bean plants are found to be free of the disease. Inaddition, the compounds of this invention are useful as antibiotics orin processes for preparing antibiotics. For example, the abovetrichloroethyl thiazoline azetidinone is active against the fungus B-trytis cinerea at a concentration of 100 micrograms/- milliliter asdetermined by an agar dilution test method described by Steers andFoltz, in Antibiotics and Chemotherapy, 9, p. 307, (1959).

In addition, the compounds of this invention are useful as intermediatesfor the preparation of thiazoles of the formula wherein R and R are asdefined above, by treatment of the thiazoline azetidinone of thisinvention with either acid or base within the range of 0 to 100C. forfrom 3 to 24 hours. The reaction is slow at room temperature and below,so that long reaction times are necessary at these temperatures. At thehigher temperatures, shorter reaction times may be used. The reaction ispreferably carried out in an inert solvent such as benzene,tetrahydrofuran, dimethylsulfoxide or dimethylformamide. It is alsopossible to use acetic acid as solvent.

The base to be used in cleaving the B-lactam ring is an inorganic basethat is a good nucleophile. Such a base is an alkali metal salt ofa weakacid having a dissociation constant of less than an alkali metalalkoxide wherein the alkoxy group contains from one to four carbonatoms, an alkali metal hydroxide or an alkaline earth metal hydroxide.Examples include sodium acetate, potassium carbonate, sodiumbicarbonate, sodium methoxide, lithium ethoxide, potassium butoxide,

sodium hydroxide. potassium hydroxide, calcium hydroxide and magnesiumhydroxide.

The acid to be used in the ring opening is a nonoxidizing organic orinorganic acid having a dissociation constant greater than 10*. Typicalexamples include hydrochloric acid, acetic acid, formic acid,trifluoroacetic acid, toluenesulfonic acid and chloroacetic acid. I

Preferred reagents for cleaving the ,B-lactam ring are sodium acetate ortrifluoroacetic acid.

The amount of acid or base should be at least one equivalent per mole ofthiazoline azetidinone and is preferably an excess of 10 to percent. Alarger excess can be used such as when an acid is employed as thesolvent, but such a large excess is unnecessary.

The thiazoles of formula V wherein R and R are as hereinabove definedare useful an antibiotics. For example, the compound of formula V whereR is phenoxyphenyl and R is methyl is active against the fungus Botrytiscinerea at a concentration of 100 meg/m1. as determined by an agardilution test method described by Steers and Foltz in Antibiotics andChemotherapy 9, p. 307 (1959). The corresponding acid is active as anantibiotic against the organism Pseudomonas solanacearum, strain X815,at a concentration of 100 meg/m1. as determined by the agar dilutiontest.

The invention is further exemplified by the following detailed examples,which are not intended to limit the scope of the invention or claimshereof.

EXAMPLE 1 A. 2S-Chloro-3R-phenylacetamido-1-[1'-(2",2,2"-trichloroethoxycarbonyl)-2-methy1-1-propenyl]-4- azetidinone To asolution of 6.975 g. 15 mm.) of B,B,B-trichloroethyl6-phenylacetamidopenicillinate in 300 ml. of methylene chloride at 76C.was added 52 ml. of a 1.0 M chlorine solution (methylene chloride). Thissolution was stirred at 76C. for 1% hours and was then allowed to warmto about 0C. Then 100 ml. of a saturated sodium bicarbonate solution wasadded to the reaction mixture. After gas evolution ceased, the organiclayer was separated washed twice with 150 ml. portions of water anddried over MgSO The solvent was then evaporated in vacuo to give 6.47 g.of the olefinic title product; nmr (CDC1 (s, 31-1),142(s, 31-1), 217 (s,21-1), 286 (q, 2H, J 6 and 12 Hz), 304 (q, 1H, J 8 and 1.5 Hz), 352 (d,1H, .1 =1.5 Hz), 397 (d, 1H, J 8 Hz), 439 112 (s, 5 Arl-l); ir (CHCl1785 cm (azetidinone C=O), 1740 cm (ester C=O), 1685 cm" (amide C=O).

B. lmino chloride of 2S-Ch1oro-3R-phenylacetamido-1-[1-2,2",2-trichloroethoxycarbonyl)-2-methy1-1-propeny1]-4- azetidinone To asolution of 2.36 g. of phosphorus pentachloride in 30 m1. of drychloroform, 2.4 m1. of quinoline was added and the resulting suspensionwas cooled to -10C. After that a solution of 4.69 g. of 2S-Chloro-3R-phenylacetamido-l-[1-(2",2",2"- trichloroethoxycarbonyl )-2-methyl-1-propeny1]-4- azetidinone in 10 ml. of dry chloroform was addedto the suspension and the solution stirred at 10C. for 30 minutes. Thesolvent and POC1 formed were distilled off under vacuum pressure and theresidue was taken up in methylene chloride and washed twice with water,and once with brine. After drying (MgSO and evaporating of the solvent,the title imino chloride (4.0 g.) was obtained as an oil; nmr (CDCI 126(s, 3H), 144 (s, 3H), 236 (s, 2H), 288 (q, 21-1, J 8 and 14 Hz), 314 (d,1H, J 2 Hz), 364 (d, 1H, J 2 Hz) and 421 cps (s, 5 ArH).

C. Thiazoline Azetidinone A solution of 5.0 g. of imino chloride frompart B hereinabove in 45 ml. of methylene chloride was saturated with HS gas and 2.8 ml. of triethylamine was added. Hydrogen sulfide gas wasintroduced into the solution for 1 hour at room temperature. The solventwas evaporated and the residue extracted with a mixture of 25 ml. ofethyl acetate and 25 ml. of ethyl ether. The salt of triethylaminehydrochloride (ca. 2.0 g.) was filtered off, the filtrate evaporated andthe residue was chromatographed over 100 g. of silica gel eluting withbenzene/ethyl acetate. Fractions (20 ml.) were collected in 18 min.period. Fractions 108-150 gave 1.45 g. of a mixture of a thiazolineazetidinone product of the formula COOCHzCC l :5

I k s CeHs -CHz EXAMPLE 2 A mixture of 974 mg. of imino chloride frompart B of Example 1, 512 mg. of potassium thioacetate, and ml. oftetrahydrofuran was stirred at room temperature for 1 hour. The mixturewas filtered, the filtrate evaporated to dryness, the residue dissolvedin methylene chloride and the solution washed twice with water andbrine, and dried (MgSO After evaporation of the solvent, the oilyresidue was chromatographed over silica gel and the desired thiazolineazetidinone product isolated as a colorless oil. Spectral analysesshowed the product to have the structure set forth in Example 1.

Similar experiments were also performed by using tetramethylammoniumthioacetate or thiolacetic acid and triethylamine instead of potassiumthioacetate and after workup and chromatography the compound having theproduct structure set forth in Example 1 was isolated.

EXAMPLE 3 Following the procedure of Example 1A. the methylphenylacetamido penicillin ester (methyl ester of penicillin G) istreated with chlorine to open the thiazolidine ring thereof at the S andC bond. The resulting product is treated with phosphorus pentachloridein the presence of quinoline, as described in Example 18. to form theimino chloride of 2-chloro-3R- phenylacetamido-l-( 1'-methoxycarbonyl-2'-methyl- 1 -propenyl)-4-azetidinone.

This new imino chloride is treated with hydrogen sulfide, as describedin Example 1C to form the thiazoline azetidinone of the formula COOCHa I(C CH:s C

CeHs-CHz 1 EXAMPLE 4 Following the procedure of Example 1A, thepnitrobenzyl ester of penicillin G (phenylmethyl penicillin) is treatedas described in Example 1A. to open the S,-C bond of the thiazoline ringmoiety thereof. The resulting product is treated with a halogenatingagent. according to the procedure described in Example 13. to form theimino chloride of 2S-chloro-3R- phenylacetamido-H 1p-nitrobenzyloxycarbonyl)- 2'-methyl-l '-propenyl]-4-azetidinone.

The new imino chloride is treated with sodium thiopropionatesubstantially according to the procedure described in Example 2 to formas product a thiazoline azetidinone of the formula COONO2 l C CH::

I a Cells-CH2 EXAMPLE 5 coocm-ocm EXAMPLE 6 Following the procedure ofExample lA the benzyl ester of phenoxyisopropyl penicillin is treatedwith bromine to open the S C;, bond of the thiazolidine ring moietythereof. The resulting product is treated with phosphorus pentabromidein place of phosphorus pentachloride according to the proceduredescribed in Example 18 to form the imino bromide of 2-bromo-3R-(2'-phenoxy-2',2'-dimethylacetamido)- l l benzyloxycarbonyl-2-methyl-l'-propenyl)-4- azetidinone.

The resulting imino bromide is treated with potassium thioacetate asdescribed in Example 2 to form as product the thiazoline azetidinone ofthe formula COOCH2 l CH v CH3 \c/ l CHa'-CCHa I 0 EXAMPLE 7 We claim: 1.A process for preparing a compound of the formula COOR' wherein R is a.C to C -alkyl,

b. C to C, cycloalkyl.

c. C. to C -alkenyl.

d. one of the above alkyl, cycloalkyl. or alkenyl groups substitutedwith C to C -alkyloxy. chlorine. bromine, cyano or carbo-C to C-alkyloxy;

I I Q wherein in each group O is hydrogen. chloro. bromo, C to C -alkyl.C to C -alkyloxy, nitro or cyano;

X is oxygen or a carbon to carbon bond, m is an integer of from O to 2.and n is an integer of from l to 7.

and R is hydrogen. C to C normal or iso-alkyl. C

to C -tert-alkyl, C to C -tert-alkenyl, C to C -tertalkynyl benzyl.methoxybenzyl. nitrobenzyl benzhydryl. phthalimido methyl.succinimidomethyl. phenacyl. 2,2,2-trichloroethyl or methoxymethyl whichcomprises treating a compound of the formula N I l I cii wherein R and Rare as defined above. Y and Z are each chlorine or bromine with hydrogensulfide or a C, to -thioalkanoic acid or an alkali metal or ammoniumsalt thereofi in the presence of a base in an sulfide is reacted withthe imino chloride of 2-chloroaprotic solvent at a temperature belowabout 70 C. 3R-phcnylacetamido-l-l l '-(2",2",2"-

2. A process as defined in claim 1 wherein R istriehloroethoxycarbonyl)-2-methyl-l '-propenyl]-4- azetidinone. CH (CH4. A process as defined in claim 2 wherein an alkali 2 ll. 2 51 metalthioacetate is reacted with the iminochloride of QZS-chloro-3R-phenylacetamidol l 2",2",2"-

trichloroethoxycarbonyl )-2-methyl-l -propenyl 1-4- whcrein Q, m, n, andX are as defined in claim 1. azetidinone.

3. A process as defined in claim 2 wherein hydrogen 1

1. A PROCESS FOR PREPARING A COMPOUND OF THE FORMULA
 2. A process asdefined in claim 1 wherein R is
 3. A process as defined in claim 2wherein hydrogen sulfide is reacted with the imino chloride of2-chloro-3R-phenylacetamido-1-(1''-(2'''',2'''',2''''-trichloroethoxycarbonyl)-2''-methyl-1''-propenyl)-4-azetidinone.
 4. A process as defined in claim 2wherein an alkali metal thioacetate is reacted with the iminochloride of2S-chloro-3R-phenylacetamido-1-(1''-(2'''',2'''',2''''-trichloroethoxycarbonyl)-2''-methyl-1''-propenyl)-4-azetidinone.